Dr. Abel is a motivated young scientist and surgeon who is committed to becoming a successful independent researcher. He completed a fellowship in urologic oncology at the MD Anderson Cancer Center, where he gained experience in basic and translational research methods. His past record of achievement is exceptional, including 11 manuscripts on renal cell carcinoma (RCC). His current position allows significant protected time for research, which he has used to develop preliminary data for this proposal. His immediate career goals focus on gaining the scientific knowledge and experience necessary to become a productive independent investigator in the field of RCC cell signaling. Long term career goals include establishing a RCC translational research program and developing therapies for RCC based on NF-?B signaling. The environment surrounding Dr. Abel is ideal for his development into an independent investigator. The Department of Urology has a history of multiple NIH funded investigators and is committed to his success. Dr. Shigeki Miyamoto is a basic scientist and world expert in NF-?B signaling who is dedicated to the close mentorship of Dr. Abel and his scientific career development. Dr. David Jarrard is a successful physician- scientist, who will serve as a co-mentor and work closely with Jason to facilitate his success in this competitive environment. Dr. Abel's career development plan takes advantage of the training opportunities, collaboration and didactic coursework which make the University of Wisconsin one of the top research institutes in the world. An estimated 65,000 patients in the US will be diagnosed with kidney cancer in 2012. Metastatic RCC is a lethal disease with few treatments, and most patients survive less than 2 years after diagnosis. RCC is a highly vascular tumor, producing angiogenic and growth factors triggered by over-expression of hypoxia inducible factors (HIFs) with recent studies demonstrating that the HIF2? subunit, specifically, plays a causal role in carcinogenesis and progression. Our preliminary studies have demonstrated a previously unknown concordant activation of NF-?B with increased HIF2? expression in RCC preclinical models and clinical samples, suggesting they are functionally related. The purpose of this proposal is to investigate the hypothesis that activation of the NF-?B/HIF2? axis promotes RCC tumor growth. In Aim 1, we will investigate the functional significance of the NF-?B/HIF2? axis using in vitro experiments. Given the probability of significant interaction from the microenvironment, we have designed Aim 2 to evaluate whether the NF-?B/HIF2? axis may indirectly promote tumor growth in RCC xenografts. In Aim 3, we will determine the clinical and pathologic outcomes associated with NF-?B activation/HIF2? expression. This proposal is innovative because it investigates NF-?B/HIF2? interaction, which is a novel pathway in RCC. Our project is significant because RCC progression is driven by HIF signaling and increased understanding of the NF-?B/HIF2? axis may allow development of new therapies for this incurable disease.